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Traditional oral preparations suffer from weak gastrointestinal resistance, rapid degradation and poor gut\u2010brain axis regulation. Here, we constructed a gastrodia elata polysaccharide\u2010functionalized dual\u2010network GEPH hydrogel via thiol\u2010maleimide click crosslinking. GEPH possesses favorable biocompatibility, regular porous microstructure and tailored rheological properties suitable for gastrointestinal delivery, showing outstanding erosion resistance and structural stability in simulated intestinal fluid. It achieves in situ gelation in the gastrointestinal tract and maintains 24\u00a0h long\u2010term retention after oral administration. GEPH modulates gut microbiota composition and metabolite profiles, repairs intestinal barrier and neuronal injury in PD mice such as\n                    <jats:italic>Corynebacterium<\/jats:italic>\n                    ,\n                    <jats:italic>CAG_95<\/jats:italic>\n                    , and\n                    <jats:italic>Akkermansia<\/jats:italic>\n                    , while regulated metabolite abundance such as 3\u2010methyl\u20104\u2010cis\u2010hydroxy\u20102\u2010butenal, Nicotinic acid, Linolenate. By regulating the TLR4\/NF\u2010\u03baB pathway and gut\u2010brain axis, it inhibits abnormal aggregation and spread of intestinal and cerebral \u03b1\u2010synuclein, alleviates neuroinflammation and neuronal apoptosis, protects dopaminergic neurons and ameliorates motor dysfunction. This study proposes GEPH as a new type of oral functionalized dual\u2010network hydrogel formulation that regulates the gut\u2010brain axis, promoting the clinical application of a new strategy for oral drug administration for gastrointestinal prevention and treatment of PD.\n                  <\/jats:p>","DOI":"10.1002\/smll.75081","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T08:40:24Z","timestamp":1785919224000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Gastrointestinal In Situ Self\u2010Assembled Gastrodia Elata Polysaccharide Hydrogel Enables Parkinson's Disease Therapy via Gut\u2010Brain Axis Modulation"],"prefix":"10.1002","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-8882-4814","authenticated-orcid":false,"given":"Tong","family":"Lei","sequence":"first","affiliation":[{"name":"Institute of Basic Theory for Chinese Medicine China Academy of Chinese Medical Sciences  Beijing China"},{"name":"Fujian Pien Tze Huang Enterprise Key Laboratory of Natural Medicine Research and Development Zhangzhou Pien Tze Huang Pharmaceutical Co., Ltd.  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